Electrochemical Oxidation of Organic Molecules at Lower Overpotential: Accessing Broader Functional Group Compatibility with Electron-Proton Transfer Mediators

Abstract

Electrochemical organic oxidation reactions are highly appealing because protons are often effective terminal electron acceptors, thereby avoiding undesirable stoichiometric oxidants. These reactions are often plagued by high overpotentials, however, that greatly limit their utility. Single-electron transfer (SET) from organic molecules generates high-energy radical-cations. Formation of such intermediates often requires electrode potentials far above the thermodynamic potentials of the reaction and frequently causes decomposition and/or side reactions of ancillary functional groups. In this Account, we show how electrocatalytic electron-proton transfer mediators (EPTMs) address this challenge. EPTMs bypass the formation of radical-cation intermediates by supporting mechanisms that operate at electrode potentials much lower (≥1 V) than those of analogous direct electrolysis reactions.The stable aminoxyl radical TEMPO (2,2,6,6-tetramethylpiperidine N-oxyl) is an effective mediator for electrochemical alcohol oxidation, and we have employed such processes for applications ranging from pharmaceutical synthesis to biomass conversion. A complementary electrochemical alcohol oxidation method employs a cooperative Cu/TEMPO mediator system that operates at 0.5 V lower electrode potential than the TEMPO-only mediated process. This difference, which arises from a different catalytic mechanism, rationalizes the broad functional group tolerance of Cu/TEMPO-based aerobic alcohol oxidation catalysts.Aminoxyl mediators address long-standing challenges in the "Shono oxidation," an important method for α-C-H oxidation of tertiary amides and carbamates. Shono oxidations are initiated by a high-potential SET step that limits their utility. Aminoxyl-mediated Shono-type oxidations have been developed that operate at much lower potentials and tolerate diverse functional groups. Analogous reactivity underlies α-C-H cyanation of secondary cyclic amines, a new method that enables efficient diversification of piperidine-based pharmaceutical building blocks and preparation of non-natural amino acids.Electrochemical oxidations of benzylic C-H bonds are commonly initiated by SET to generate arene radical cations, but such methods are again plagued by large overpotentials. Mediated electrolysis methods that promote hydrogen-atom-transfer (HAT) from benzylic C-H bonds to Fe-oxo species and phthalimide N-oxyl (PINO) support C-H oxygenation, iodination, and oxidative-coupling reactions. A complementary method merges photochemistry with electrochemistry to achieve amidation of C(sp³)-H bonds. This unique process operates at much lower overpotentials compatible with diverse functional groups.These results have broad implications for organic electrochemistry, highlighting the importance of "overpotential" considerations and the prospects for expanding synthetic utility by using mediators to bypass high-energy outer-sphere electron-transfer mechanisms. Principles demonstrated here for oxidation are equally relevant to electrochemical reductions.

Figure 1.

Schematic diagrams and simplified energy profiles for A) direct electrolysis reactions initiated by SET and B) mediated (indirect) electrolysis reactions. Med = Mediator. In both cases, the energy diagrams are simplified to show only the barriers involving the highest energy transition state (or activated complex, for ET steps) in the multistep reactions.

Figure 2.

Different mediated systems and representative mediators. Prod. = Product. ET = Electron Transfer. HAT = Hydrogen Atom Transfer. H⁻T = Hydride Transfer.

Figure 3.

Chemical (A) and electrochemical (B) alcohol oxidation with aminoxyls as catalysts and the proposed mechanism for TEMPO⁺-mediated alcohol oxidation under acidic/basic conditions (C).

Figure 4.

Electrochemical alcohol oxidation with aminoxyl mediators. Diverse aminoxyls that may be used as electrochemical mediators (A); ACT-mediated electrochemical oxidation of primary alcohols to carboxylic acids relevant to pharmaceuticals (B), including representative substrates (i); effect substrate structure on alcohol and aldehyde oxidation rate (ii); and implementation of the method in a synthetic route toward levetiracetam (iii); and ACT-mediated electrochemical oxidation of primary alcohols in lignin, enabling efficient depolymerization (C). Adapted with permission from ref. . Copyright 2019 American Chemical Society.

Figure 5.

Pyrene–TEMPO-mediated electrochemical alcohol oxidation. A) Comparison of bulk electrochemical benzyl alcohol oxidation with pyrene-TEMPO and ACT; B) Selected substrate scope for pyrene–TEMPO-mediated electrochemical alcohol oxidation. Adapted with permission from ref . Copyright 2017 John Wiley and Sons.

Figure 6.

Mechanistic features of Cu^II/TEMPO-mediated alcohol oxidation.

Figure 7.

Comparison of Cu^II/TEMPO and TEMPO⁺ mediated electrochemical alcohol oxidation in CH₃CN. bpy = 2,2’-bipyridine. Reprinted with permission from ref . Copyright 2016 Springer Nature Publishing Group.

Figure 8.

Aminoxyl-mediated Shono-type oxidation. A) Mechanism of the conventional Shono oxidation and example of the limitation in substrate scope arising from the high overpotential. B) Aminoxyl-mediated Shono-type oxidation, with the structure of effective mediators and the mechanism. C) Selected substrates of mediated Shono-type oxidation.

Figure 9.

A) Intermolecular additive screening of aminoxyl-mediated Shono-type oxidation; B) Oxidation potential of organic molecules, including aminoxyl, carbamate and additives in (A). Reprinted with permission from ref . Copyright 2018 John Wiley and Sons.

Figure 10.

ABNO-mediated α-cyanation of piperidine. A) Proposed mechanism and B) potential traces of constant current electrolysis under different conditions. Adapted with permission from ref . Copyright 2018 American Chemical Society.

Figure 11.

Selected substrate scope for ABNO-mediated α-C–H bond cyanation of piperidines and subsequent hydrolysis of cyanides to unnatural amino acids.

Figure 12.

Use of high-valent Fe complexes for oxidation of benzylic C–H and/or alcohol substrates to ketones.

Figure 13.

Simplified mechanism depicting C–H oxygenation with a Co/NHPI catalyst system in the presence of O₂.

Figure 14.

A) Selected substrate scope for Co/NHPI-catalyzed aerobic C–H bond oxygenation; B) NHPI-mediated electrochemical aerobic C–H bond oxygenation and comparison with chemical conditions.

Figure 15.

NHPI-mediated electrochemical C–H bonds iodination and in-situ methylarene iodination/alkylation of pyridine: mechanism and representative substrate scope.

Figure 16.

Comparison of PINO-mediated HAT and direct-ET initiated C−H oxidation of methylarenes. Reprinted with permission from ref . Copyright 2018 American Chemical Society.

Figure 17.

Different electrochemical strategies for dehydrogenative amination of sp³ C–H bonds (A-C) and comparison of their applied potential in the context of functional group compatibility (D).

Figure 18.

Selected substrate scope for iodide-mediated dehydrogenative amination via merging photochemistry with electrochemistry.